The 6-O-methylation of various erythromycin derivatives has been reported in several patents or published applications. U.S. Pat. No. 4,496,717 (issued Jan. 25, 1985) describes the methylation of a 2'-O-,3'-N-dibenzyloxycarbonyl derivative of erythromycin by reaction with a methylating reagent in the presence of a base such as an alkali metal hydride or an alkali metal amide. U.S. Pat. No. 4,670,549 (issued Jun. 2, 1987) describes the reaction of a quaternary salt of an erythromycin A 9-oxime with a methylating reagent in the presence of a base such as an alkali metal hydride, hydroxide or alkoxide. U.S. Pat. No. 4,672,109 (issued Jun. 9, 1987) describes the reaction of an erythromycin A 9-oxime with a methylating reagent in the presence of a base such as an alkali metal hydride or hydroxide. European Application EP 260938 (published Mar. 23, 1988) describes 6-O-methylerythromcyin derivatives prepared by the reaction of 2'-silylated erythromycin A 9-oximes with a methylating reagent in the presence of a base, such as an alkali metal hydride, hydroxide or alkoxide, that is said to prevent undesirable quaternary salt formation. U.S. Pat. No. 4,990,602 (issued Feb. 5, 1991) describes additional 6-O-methylerythromcyin erythromycin A derivatives (more broadly substituted at the oxime position than those of EP 260938) prepared by the reaction of such 2'-silylated erythromycin 9-oxime derivatives with a methylating reagent in the presence of a base such as an alkali metal hydride, hydroxide or alkoxide, also with the stated intention of preventing undesirable quaternary salt formation. While the U.S. Pat. No. 4,990,602 and the EP 260938 application point out the desirability of preventing quaternary salt formation, there remains a need for alternative methods for improving yields.
The continued appearance of new patents directed to 6-O-methyl erythromycin compounds is an indication of the importance of and the continuing efforts towards preventing unwanted side-reactions and to increasing the yield of the desired antibiotic compounds (e.g., clarithromycin).
In general, the process for making clarithromycin can be thought of as a four-step procedure beginning with erythromycin A as the starting material:
Step 1: optionally protect the 9-oxo group with an oxime;
Step 2: protect the 2' and 4" hydroxyl groups;
Step 3: methylate the 6-hydroxyl group;
Step 4: deprotect at the 2', 4" and 9-positions.
We have now found that higher yields of 6-O-alkyl erythromycin derivatives may be obtained and by-product compounds reduced by means of a 6-O-alkylation procedure that utilizes a weak organic base in the presence of a strong base. This alkyation step corresponds to the general Step 3 referred to above.
This procedure is especially useful when a mixture of hydroxy-protected erythromycin derivatives (and especially those protected with silyl compounds, eg., trimethylsilyl) is to be methylated. Such mixtures of hydroxy-protected erythromycin derivatives (i.e., mixtures of the 2'-mono-, 4"-mono, and 2',4"-bis-protected derivatives) may be produced during large scale preparations (i.e., in Step 2 referred to above) if the bis-protection is not fully achieved. The ability to perform the alkylation on a mixture of hydroxy-protected compounds is also a distinct advantage, as costly separation steps may be avoided.